Because radiation therapy relies upon the often small margin of differential radiosensitivity between normal and malignant tissue, the radiation dose delivered must be carefully balanced to destroy all malignant cells while sparing the surrounding normal tissue. WR-2721 is an effective radioprotectant for the parotid gland and could be important in preventing "dry mouth" in head and neck radiotherapy patients. The sympathomimetic drug isoproterenol is also protective but has the great advantage of current clinical availability, which WR-2721 does not. Isoproterenol functions by activating the membrane b-receptor generating cAMP. cAMP had been suggested as a radioprotectant and we lent further support by protecting the parotid with exogenously given db, cAMP. This proposal seeks to develop new strategies of parotid protection using WR-2721 and isoproterenol. Specifically, since WR-2721 and isoproterenol have toxicities at the doses used but function by different mechanisms, we would like to combine both drugs, at lower doses, while retaining adequate protection. Also, multiple doses of isoproterenol massively enlarge the parotid. We hope that such an enlarged gland can be protected by WR-2721. Our observations of protection by WR-2721 suggested that secretion was somehow protective and studies with the sympathetic secretogogue isoproterenol and cAMP support a role for the sympathetic nervous system through a mechanism which includes cAMP. Now we will address the question of whether secretion induced by parasympathomimetic drugs could also provide protection and, if so, is there a membrane receptor involved. Among the strategies used to implicate cAMP in many of their reputed activities is the ability to produce an effect when endogenously produced cAMP is elevated by prevention of its hydrolysis by phosphodiesterase (PDE) inhibitors. We propose to produce radioprotection by the use of a variety of phosphodiesterase inhibitors, either alone or in combination with cAMP-elevating isoproterenol. In addition, we will determine whether the tumor radiosensitizer Misonidazole is compatible with the radioprotectors isoproterenol and cAMP. Our ultimate goal is to find alternative radioprotectors and strategies in the hope that they will be compatible with current or future tumor radiosensitizers so as to improve the therapeutic index.